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Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics **
Author(s) -
Sutherland Mathew,
Li Alice,
Kaghad Anissa,
Panagopoulos Dimitrios,
Li Fengling,
Szewczyk Magdalena,
Smil David,
Scholten Cora,
Bouché Léa,
Stellfeld Timo,
Arrowsmith Cheryl H.,
Barsyte Dalia,
Vedadi Masoud,
Hartung Ingo V.,
Steuber Holger,
Britton Robert,
Santhakumar Vijayaratnam
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100018
Subject(s) - biochemistry , arginine , chemotype , biology , chemistry , amino acid , food science , essential oil
Protein arginine N ‐methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure‐based design of a new class of alanine‐containing 3‐arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds.